Breaking the cycle of intergenerational transmission of alcohol dependence from women alcoholics to their offspring through intervention requires identification of relevant mediating and moderating risk/protective factors. Because we need a better understanding of how to identify those children at highest risk, study of offspring of parents with the most severe form of the disorder is needed. A "double proband" methodology was first developed in our laboratory to select families with more severe cases of male alcoholism (early onset, high familial aggregation). Using a double proband methodology to identify a severe form of alcoholism in women, we have now completed recruitment of a sample of mothers and their offspring for longitudinal follow-up and successfully followed children with good retention (80% at the fourth annual visit). To date, offspring of these women alcoholics have shown significantly earlier onset to begin regular drinking, and have an earlier onset of depressive disorders, conduct disorders and "any psychiatric disorder." The first goal of the renewal effort is to model psychiatric outcome by age 18 through identification of important interactions between a quantified estimate of familial risk, neurobiological indicators (e.g., P300 developmental trajectories), prenatal use of alcohol/drugs in mothers, and a number of environmental factors including the mothers' continued use of alcohol/drugs. Establishing which predictors influence the age of onset to begin drinking, a variable that is highly correlated with alcohol dependence outcome in national surveys will be determined using a similar set of environmental and familial/genetic predictors. Finally, a young-adult follow-up involving participants for whom multiple waves of child/adolescent data has been collected will enable us to study the effect of these factors on outcome, including substance dependence by young adulthood. Young adulthood has been identified as a period of considerable importance in that many individuals "mature out" of abusive patterns of use while others may go on to severe problems. Studying these young adults will also allow us to capture changes in drinking and drug use during young adulthood and concomitant environmental changes (e.g., marriage, first career-related job) during this period as they relate to risk status and its interaction with other familial/genetic and other environmental factors.